tbuckley/cabot-search huggingface dataset:
Abstract 4186: Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research
Authors: Linsey Eldridge, Elise Garton, Kalina Duncan, Satish Gopal
Journal: Cancer Research (2023)

Abstract Introduction: We conducted a bibliometric analysis to assess authorship of recent publications involving collaborations in low- and middle-income countries (LMICs) supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH). Methods: We identified active NCI grants awarded directly to LMIC institutions or to US institutions with a collaborator site or sites exclusively in LMICs between 2015-2019 in NIH Query View Report (QVR). Grants were linked to resulting publications using Dimensions for NIH. Because grants may have been active in 2015 while beginning in earlier years, we analyzed any linked publications from 2011 to 2020. Publications with missing author information were excluded. Author institutional affiliation was used to classify author country income level as defined by the World Bank. Authors with multiple institutional affiliations from a high-income country (HIC) and LMIC were classified as such. Relative citation ratio (RCR) and Altmetric data from Dimensions were used to compare citation impact measures using the Wilcoxon rank sum test. Results: NCI funded 159 grants to US institutions exclusively with LMIC collaborators and five awards directly to institutions in LMICs from 2015 to 2019, resulting in 2,428 publications between 2011 and 2020, of which 49% had at least one author affiliated with an LMIC institution. Of all publications, 78% and 83% had a first and last author with high-income country (HIC) affiliation, respectively. Publications with HIC-affiliated last authors had significantly higher median RCR and Altmetric attention scores than publications with LMIC-affiliated last authors (p=0.0134 and p=0.0004, respectively). Publications with HIC-affiliated first authors had significantly higher Altmetric scores than publications with LMIC-affiliated first authors (p=0.001). Conclusion: LMIC-affiliated authors are represented on only approximately half of publications resulting from NCI grants awarded directly to LMIC institutions or to US institutions with LMIC collaborators, and rarely in the first or last author position. LMIC-affiliated authors also receive less bibliometric attention when represented. Increased scientific capacity and more equitable collaboration should be critical priorities for the cancer research community working in LMICs moving forward. Citation Format: Linsey Eldridge, Elise Garton, Kalina Duncan, Satish Gopal. Underrepresentation of low- and middle-income country affiliated authors in NCI-supported cancer research. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4186.
Abstract 3217: Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO)
Authors: Doaa Attia, Ran Zhao, Alok A. Khorana, Prandya Patil
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibitors with or without chemotherapy form the backbone of treatment for patients with advanced NSCLC without an actionable driver mutation. Emerging literature shows that ICIs increase the risk of venous thromboembolism (VTE), which is a major cause of death in patients with NSCLC. The mechanism is yet to be elucidated but is likely secondary to inflammation. Since chemotherapy is immunosuppressive, we sought to understand if the addition of chemotherapy to ICIs impacted the incidence of VTEs. Methods: We performed a retrospective cohort study to evaluate thromboembolic outcomes in patients diagnosed with advanced NSCLC between 2012 and 2018 and treated with either ICIs or chemo immunotherapy at Cleveland Clinic Foundation. Diagnosis of thrombotic events (TE) (arterial/deep vein thrombosis and/or pulmonary embolism) was confirmed by imaging. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Odds of developing TE was estimated and compared between ICI and ChemoIO groups, using Fisher's Exact Test. Results: A total of 367 NSCLC patients (242 pts on ICI only and 125 pts on ChemoIO regimen), were identified with a median age 65 years ( range 58-72), 52% were men, 82% white, 85.3% smokers, 91.8% had ECOG ≤2, 73 % had adenocarcinoma and 18% had squamous cell carcinoma, 34% with brain metastasis and the distribution of PDL1expression was as follows- &amp;lt;1 (26.4%), 1-49% (48%) and ≥50% (25.6%). Adjusted response rates to treatment were (N, %): Complete Response (CR) (6/367, 1.9%), Partial Response (PR) (96/367, 30%), Stable Disease (SD) (76/367, 24%) and PD (143/367, 45%). TE was detected in 19% of the cohort (n=70) (8.4% DVT, 4.9% PE, 5.2 % both, and 0.5 % arterial TE. Rate of TE in NSCLC pts on ICI alone was 18% (44/242) Vs. 21% (26/125) for those on ChemoIO (OR 1.5, 95% CI 0.66-2.1, P 0.6). Development of TEs was not associated with survival differences with either regimen (P &amp;gt;0.05). Conclusion: Rates of TE were high in patients with advanced NSCLC who received ICI therapy, but no different if treated with ICIs alone or ChemoIO. Further studies to better understand the pathophysiology of TE in patients treated with ICIs might allow us to identify subgroups of patients that are at the highest risk for TEs. Citation Format: Doaa Attia, Ran Zhao, Alok A. Khorana, Prandya Patil. Risk of thromboembolism in patients with non-small lung cancer (NSCLC) treated with immune check point inhibitors (ICIs) versus chemoimmunotherapy (ChemoIO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3217.
Abstract 3137: Somatic structure variants as a biomarker to predict immune checkpoint inhibitor response by generating anti-tumour antigen
Authors: Hongui Cha, Benjamin Simpson, Charles Swanton, Kevin Litchfield, Genomics England Research Consortium
Journal: Cancer Research (2023)

Abstract The introduction of checkpoint inhibitors (CPI) has revolutionised the treatment of advanced cancers, which act to ameliorate the anti-tumour response through blocking inhibitive immune checkpoint receptors. Whole-exome sequencing (WES) based estimates of tumour mutational burden (TMB) has been robustly associated with response to CPI therapy across multiple tumour types and a threshold of ≥10 mutations per megabase (Mb) is now an FDA-approved biomarker for treatment with pembrolizumab. However, studies to date have been limited to whole exome sequencing (WES), with no data yet reported on the utility of whole genome sequencing (WGS) as a biomarker to predict CPI response. WGS data can identify non-coding alterations which impact the expression of immune regulatory genes, variants likely to form non-coding epitopes, including novel open reading frame mutations especially structure variants (SV). Here, we have identified a pan-cancer cohort of n=364 patients treated with CPI from Genomics England 100,000 Genomes Project (GEL). We find that SV burden is highly associated with worse CPI response (HR =1.3 (1.0-1.8) , p-value = 0.037) and high SV burden group have low tumour-infiltrating lymphocyte (TIL) score (P-value &amp;lt; 0.0001). However, we found that patients who have high proportion of SV derived neoantigen group improved overall survival (HR = 0.44 (0.27-0.73) , p-value = 0.002). In addition, enhancer region alteration of antigen present gene was observed in 43 patients (12%) and was associated with worse CPI response. (HR = 1.5 (1.0-2.2), P-value = 0.034). We further explored the SV derived neoantigen generate neoantigen-specific T cell response. Summary of Cox Model from structure variant Variables No. patients HR (95% CI) P Sex Female 164 Male 200 1.15 ( 0.87-1.52) 0.3285 Cancer Type Others 59 Lung 88 1.39 (0.91-2.14) 0.1255 Melanoma 155 0.84 (0.56-1.28) 0.4267 Renal 62 0.84 (0.52-1.38) 0.495 TMB estimated WGS 364 0.98 (0.97-0.99) 0.0036 SV burden Low 182 High 182 1.36 (1.02-1.81) 0.0358 Proportion of anti-tumour antigen from SV Low 49 High 47 0.48 (0.29-0.8) 0.0045 antigen non-generate 268 0.49 (0.35-0.7) &amp;lt; 0.0001 Citation Format: Hongui Cha, Benjamin Simpson, Charles Swanton, Kevin Litchfield, Genomics England Research Consortium. Somatic structure variants as a biomarker to predict immune checkpoint inhibitor response by generating anti-tumour antigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3137.
Abstract 4370: How much time is needed to complete quality of life assessments in oncology trials? - Metadata analysis
Authors: Jowita Marszewska, Lindsay Hughes
Journal: Cancer Research (2023)

Abstract Introduction: Digitalization in clinical trials introduced electronic data collection. Participants in diverse environments can use electronic devices to report their experiences with the drug by completing patient reported outcome assessments (ePROs). Quality of life (QOL) reports describe how a patient feels or functions during a treatment with a new drug. For oncology trials, QOL data is needed to prove the treatment effect and support a labeling claim. Methods: The literature search in the Web of Science for articles containing QOL keyword found ten articles with the highest number of citations. QOL instruments relevant to cancer research were identified based on the literature search. Form completion times corresponding to the cancer-specific instruments were identified and analyzed using a metadata of 948 instruments and 17,234,458 assessment submissions. Results: Three general QOL measures in oncology trials were identified: the EORTC Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30), Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F), and SF-36 Health Survey (SF-36). Median times of form completion in seconds (s) increased in the following order: FACIT-F &amp;lt; EORTC QLQ-C30 &amp;lt; SF-36v2 and were equal to 105 s &amp;lt; 213 s &amp;lt; 386 s. Metadata analysis showed that participants spent less than two minutes on completion of the FACIT-F assessment, which is only 18% of the estimated completion time of 10 minutes. Metadata analysis showed that it took participants three and a half minutes to complete the EORTC QLQ-C30 assessment, which is roughly one third of the estimated completion time of 11 minutes. The completion time for SF-36v2 fell within the estimated range of 5 to 10 minutes. Conclusions: Properly selected QOL instruments facilitate collection of the right data for demonstration of a treatment benefit. It is recommended to include a general oncology and a disease specific QOL instrument to show the treatment’s success of improving patient’s QOL. At the same time, the completion of the instruments should not be burdensome considering disease progression characteristic for oncology studies. Citation Format: Jowita Marszewska, Lindsay Hughes. How much time is needed to complete quality of life assessments in oncology trials? - Metadata analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4370.
Abstract 665: Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma
Authors: Siyu Sun
Journal: Cancer Research (2023)

Abstract Overexpression of repetitive RNA is an emerging hallmark of human cancers. These diverse repetitive elements, including SINEs (Short Interspersed Nuclear Elements) and LINEs (Long Interspersed Nuclear Elements), can mimic viruses by replicating in the genome through retrotransposition and displaying pathogen-associated molecular patterns, potentially triggering inflammatory responses. However, our knowledge of how specific repeats affect tumor evolution and shape the tumor immune microenvironment in a pro- or anti-tumorigenic manner remains incomplete. We integrated evolutionary analysis on whole genome and total RNA sequencing data from a unique cohort of multiregion-sampled human primary and metastatic pancreatic ductal adenocarcinoma (PDAC). We find that the more recently evolved SINEs are more likely to form double-strand RNAs (dsRNAs), a structure known to stimulate innate immune response. Consistently, these younger SINEs are highly associated with a RIG-I associated type-I interferon signature. LINE-1 (L1) retrotransposition activity in these samples tracks with tumor phylogenetic branching and is depended on the status of TP53 mutations, supporting active differential surveillance of L1 mobility by mutant TP53 during tumor evolution. Lastly, we discovered that immunostimulatory SINE expression is anti-correlated with both ADAR1 expressions, exonuclease DIS3 expression, and L1 retrotransposons activity, suggesting a cooperative relationship between ADAR1 and L1 activity in regulating immunogenic SINE expression. We propose that pancreatic tumors modulate immunogenic SINE abundance to their pro-tumorigenic inflammatory advantage through hyperactive L1 activity via accelerated exonuclease degradation when ADAR1 is not activated. Our analysis illustrates for the first time the evolutionary role of dark matter genomic repeats in allowing tumors to actively leverage viral-like innate immune responses to manipulate their immune microenvironment for selective advantage. Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve with the immune microenvironment in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 665.
Abstract 788: Novel multiplex methylation-specific qPCR strategy for early CRC detection
Authors: Yun Bao, Heng Wang, Peter Vu, Grace Zhao, Shengrong Lin
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) can be cured if detected early. Analysis of abnormalities in cfDNA methylation is an emerging and powerful strategy for early cancer detection. Recently, targeted methylation NGS methods have shown encouraging performance in CRC detection, but their high cost and complicated workflow can be challenging for many clinical settings. At the same time, the alternative, single methylation biomarker PCR assays, demonstrate limited sensitivity and specificity. An accurate, accessible and affordable assay ideal for clinical applications requires an easily scalable set-up and a set of high quality biomarkers providing sufficient predictive power. We aim to develop an assay fulfilling the CMS definitive performance guideline of LBx CRC screening – at least 74% sensitivity and 90% specificity. Here we report the development of a novel multiplex methylation-specific qPCR (MMS-qPCR) strategy for early CRC detection. Previously, we established detailed methylation profiles of our proprietary CRC targeted methylation sequencing panel with 560 biomarkers, based on more than 500 plasma samples of both healthy controls and CRC patients of various stages. We selected 9 biomarkers that are both highly sensitive and specific for CRC. These 9 markers show methylation signatures prevalent in patients and have very low noise in healthy controls. Along with one reference gene, the 9 CRC hypermethylated biomarkers can be multiplexed and analyzed in a single methylation-specific qPCR reaction. Analytical sensitivity and specificity were determined using a model system where hypermethylated DNA molecules were spiked into normal cell free DNA background at various percentages. With 10 ng of input, we can detect a single copy of the hypermethylated genome, achieving 0.006% limit of detection. Plasma samples from 10 stage I and 11 stage II CRC patients as well as 104 age-matched control subjects were subjected to the PCR analysis to yield a specificity of 96% and detection rate of 50% for stage I and 81% for stage II. The total turnaround time for analysis was &amp;lt;4 hours including DNA isolation, bisulfite conversion and qPCR analysis. The MMS-qPCR described here provides an accurate, accessible, and affordable liquid biopsy assay for the early detection of CRC. The same development strategy can also be applied to many other cancer types. Citation Format: Yun Bao, Heng Wang, Peter Vu, Grace Zhao, Shengrong Lin. Novel multiplex methylation-specific qPCR strategy for early CRC detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 788.
Abstract 192: A novel and rapid patient-derived organoid breast cancer platform for precision medicine
Authors: David M. Graham, Gabrielle Rupprecht, Eric D. Bankaitis, Jeremy M. Force, Wylie Watlington, Steven W. Metzger, Xiling Shen, David Hsu
Journal: Cancer Research (2023)

Abstract An increasing number of studies performing correlative drug screens on patient-derived organoids (PDO) are revealing enormous potential for these models in predicting patient response to therapy. Despite this, their future use in a clinical setting is hindered by intrinsic limitations of PDO models, namely low success rates in establishing growing cell cultures from tumor tissue samples and long return times for drug response data that fall outside timescales of clinical actionability. To address these limitations, we leveraged technological advances in emulsion-based microfluidics and droplet generators to develop MicroOrganoSpheres (MOS) - microscale environments containing tumorspheres that retain structural, cellular, and genetic properties of an individual patient’s diseased tissue. Here, we focused on generating MOS from breast cancer tissue biopsies and resections across different subtypes of breast cancer. We established over 30 unique patients’ breast MOS samples at an average of 80% success, with the majority of these samples being hormone receptor positive (ER+/PR+) - the most clinically lethal and challenging subtype to establish. We evaluated MOS dose-responses across several first line standard of care chemotherapies for breast cancer. For this, we created a semi-automated workflow paired with high-content imaging for quantifying dose responses and tracking longitudinal cell dynamics during dosing. We generated dose response data for MOS samples, being able to move from primary tissue samples to MOS to drug dosing data within a clinically relevant timescale of 2-3 weeks. We conclude that our platform demonstrates the feasibility of 1) efficiently establishing MOS from breast cancer patient tumor samples from different subtypes and 2) performing drug dosing studies on these samples with improved turnaround times that enable clinical actionability for the patient. Together, these findings provide a foundation for evaluating this technology as a diagnostic tool in future clinical settings. Citation Format: David M. Graham, Gabrielle Rupprecht, Eric D. Bankaitis, Jeremy M. Force, Wylie Watlington, Steven W. Metzger, Xiling Shen, David Hsu. A novel and rapid patient-derived organoid breast cancer platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 192.
Abstract 483: Hederacolchiside A1 inhibits autophagy via CTSC inhibition and inhibits growth in colon cancer
Authors: Solbi Kim, Eunji Kim, Minju Han, Youn Seo Oh, Sora Kang, Heung Jin Jeon, Hyo Jin Lee
Journal: Cancer Research (2023)

Abstract Background: Autophagy is a normal regulatory process that degrades non-functional or unnecessary cellular components. The degradation of components provides materials for the synthesis of cellular components and, during tumor development, may provide energy. Therefore, autophagy regulation may have potential therapeutic uses in oncology. The triterpenoid saponin hederacolchiside A1 (HA1) has potent antitumor effects; however, its role in autophagy is still unknown. Methods: In the present study, we used human colon cancer cells (SW480 and HT29) and mouse colon cancer cells (CT26) for the main experiments, and several additional cancer cell lines for other experiments. To assess the autophagy dysregulation caused by HA1, we evaluated the protein expressions of two autophagy markers (LC3 and SQSTM1) using Western blotting and the changes in organelles using LC3 puncta assay and transmission electron microscopy. We compared the effects of HA1 and other autophagy inhibitors. Additionally, we compared the HA1-induced decrease in cathepsin C (CTSC) expression in tumors and non-tumors using publicly available data. The effect of HA1 on tumor growth was evaluated in vitro using a three-dimensional spheroid model and patient-derived colon organoids, and in vivo based on tumor growth in a subcutaneous injection mouse model. Results: HA1 treatment resulted in marked vacuolization of colon and other cancer cells. Additionally, autophagy was induced by the accumulation of LC3-II and SQSTM1. These findings were supported by increased LC3 puncta and abnormal organelle morphology. Compared to treatment with other autophagy inhibitors, HA1 treatment resulted in the formation of distinct vacuoles and increased LC3 and SQSTM1, similar to chloroquine treatment. The publicly available data showed that the lysosomal protease CTSC was increased in several cancers, including colon cancer, compared to the normal tissues. Furthermore, HA1 decreased the CTSC expression and enzymatic activity independently of the proteasome degradation, resulting in autophagy dysregulation and, subsequently, autophagy flux inhibition. HA1 inhibited cell growth and induced cell cycle arrest in the two-dimensional culture, three-dimensional spheroids, patient-derived colon cancer organoids, and the in vivo experiments. Conclusion: HA1 inhibits cell growth and induces autophagy dysregulation. Therefore, HA1 may be a potential therapeutic agent in colon cancer. Citation Format: Solbi Kim, Eunji Kim, Minju Han, Youn Seo Oh, Sora Kang, Heung Jin Jeon, Hyo Jin Lee. Hederacolchiside A1 inhibits autophagy via CTSC inhibition and inhibits growth in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 483.